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https://www.readbyqxmd.com/read/28098447/the-stories-tryptophans-tell-exploring-protein-dynamics-of-heptosyltransferase-i-from-escherichia-coli
#1
Joy M Cote, Carlos Andres Ramirez-Mondragon, Zarek S Siegel, Daniel Joseph Czyzyk, Jiali Gao, Yuk Yin Sham, Ishita Mukerji, Erika A Taylor
Heptosyltransferase I (HepI) catalyzes the addition of a single L-glycero-β-D-manno-heptose sugar (heptose) onto the membrane incorporated Kdo2-Lipid A as part of the biosynthesis of the core region of lipopolysaccharide (LPS). Gram-negative bacteria with gene knockouts of HepI have reduced virulence with enhanced susceptibility to hydrophobic antibiotics, making design of inhibitors against HepI of interest. Previous studies have shown that HepI protein dynamics are partially rate limiting, and therefore disruption of protein dynamics might provide a new strategy for inhibiting HepI...
January 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28098411/an-efficient-basket-trial-design
#2
Kristen M Cunanan, Alexia Iasonos, Ronglai Shen, Colin B Begg, Mithat Gönen
The landscape for early phase cancer clinical trials is changing dramatically because of the advent of targeted therapy. Increasingly, new drugs are designed to work against a target such as the presence of a specific tumor mutation. Because typically only a small proportion of cancer patients will possess the mutational target, but the mutation is present in many different cancers, a new class of basket trials is emerging, whereby the drug is tested simultaneously in different baskets, that is, subgroups of different tumor types...
January 18, 2017: Statistics in Medicine
https://www.readbyqxmd.com/read/28097316/evaluation-of-structural-progression-in-arrhythmogenic-right-ventricular-dysplasia-cardiomyopathy
#3
Thomas P Mast, Cynthia A James, Hugh Calkins, Arco J Teske, Crystal Tichnell, Brittney Murray, Peter Loh, Stuart D Russell, Birgitta K Velthuis, Daniel P Judge, Dennis Dooijes, Ryan J Tedford, Jeroen F van der Heijden, Harikrishna Tandri, Richard N Hauer, Theodore P Abraham, Pieter A Doevendans, Anneline S J M Te Riele, Maarten J Cramer
Importance: Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce. Objectives: To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C...
January 11, 2017: JAMA Cardiology
https://www.readbyqxmd.com/read/28097235/a-patient-derived-xenograft-platform-to-study-brca-deficient-ovarian-cancers
#4
Erin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H Mach, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L Nathanson, Fiona Simpkins
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28096903/anxiety-and-depression-symptoms-among-women-attending-group-based-patient-education-courses-for-hereditary-breast-and-ovarian-cancer
#5
Wenche Listøl, Hildegunn Høberg-Vetti, Geir Egil Eide, Cathrine Bjorvatn
BACKGROUND: Women carrying BRCA-mutations are facing significant challenges, including decision making regarding surveillance and risk-reducing surgery. They often report that they are left alone with these important decisions. In order to enhance the genetic counselling session we organized a group-based patient education (GPE) course for women with BRCA-mutations. The study aims were to characterize women attending a group-based patient education (GPE) course for hereditary breast and ovarian cancer, consider the usefulness of the course, evaluate symptoms of anxiety and depression among the participants, and finally investigate whether their levels of anxiety and depression changed from before to after the course session...
2017: Hereditary Cancer in Clinical Practice
https://www.readbyqxmd.com/read/28096902/functional-characterization-of-the-active-mutator-like-transposable-element-muta1-from-the-mosquito-aedes-aegypti
#6
Kun Liu, Susan R Wessler
BACKGROUND: Mutator-like transposable elements (MULEs) are widespread with members in fungi, plants, and animals. Most of the research on the MULE superfamily has focused on plant MULEs where they were discovered and where some are extremely active and have significant impact on genome structure. The maize MuDR element has been widely used as a tool for both forward and reverse genetic studies because of its high transposition rate and preference for targeting genic regions. However, despite being widespread, only a few active MULEs have been identified, and only one, the rice Os3378, has demonstrated activity in a non-host organism...
2017: Mobile DNA
https://www.readbyqxmd.com/read/28096700/sequential-combination-chemotherapy-of-dacarbazine-dtic-with-carboplatin-and-paclitaxel-for-patients-with-metastatic-mucosal-melanoma-of-nasal-cavity-and-paranasal-sinuses
#7
W Omata, A Tsutsumida, K Namikawa, A Takahashi, K Oashi, N Yamazaki
By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma...
2017: Clinical Medicine Insights. Case Reports
https://www.readbyqxmd.com/read/28096458/more-severe-disease-and-slower-recovery-in-younger-patients-with-anti-3-hydroxy-3-methylglutaryl-coenzyme-a-reductase-associated-autoimmune-myopathy
#8
Eleni Tiniakou, Iago Pinal-Fernandez, Thomas E Lloyd, Jemima Albayda, Julie Paik, Jessie L Werner, Cassie A Parks, Livia Casciola-Rosen, Lisa Christopher-Stine, Andrew L Mammen
OBJECTIVE: To study disease severity and response to therapy in a large cohort of patients with anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-associated myositis. METHODS: Muscle strength, creatine kinase levels and treatments were assessed in anti-HMGCR-positive patients at each clinical visit. Univariate and multivariate analyses were used to analyse the influence of clinical characteristics on strength and the change in strength over time. Whole exome sequencing was performed in a subset of patients...
January 17, 2017: Rheumatology
https://www.readbyqxmd.com/read/28095902/identification-of-positive-selection-in-genes-is-greatly-improved-by-using-experimentally-informed-site-specific-models
#9
Jesse D Bloom
BACKGROUND: Sites of positive selection are identified by comparing observed evolutionary patterns to those expected under a null model for evolution in the absence of such selection. For protein-coding genes, the most common null model is that nonsynonymous and synonymous mutations fix at equal rates; this unrealistic model has limited power to detect many interesting forms of selection. RESULTS: I describe a new approach that uses a null model based on experimental measurements of a gene's site-specific amino-acid preferences generated by deep mutational scanning in the lab...
January 17, 2017: Biology Direct
https://www.readbyqxmd.com/read/28095480/inference-of-candidate-germline-mutator-loci-in-humans-from-genome-wide-haplotype-data
#10
Cathal Seoighe, Aylwyn Scally
The rate of germline mutation varies widely between species but little is known about the extent of variation in the germline mutation rate between individuals of the same species. Here we demonstrate that an allele that increases the rate of germline mutation can result in a distinctive signature in the genomic region linked to the affected locus, characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background of haplotypes carrying a typical proportion of derived alleles...
January 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28094565/the-decline-in-hiv-1-drug-resistance-in-heavily-antiretroviral-experienced-patients-is-associated-with-optimized-prescriptions-in-a-treatment-roll-out-program-in-mexico
#11
Juan J Calva, Silvana Larrea, Marco A Tapia-Maltos, Mauricio Ostrosky-Frid, Carolina Lara, Pedro Aguilar-Salinas, Héctor Rivera, Juan P Ramírez
A decrease in the rate of acquired antiretroviral (ARV) drug-resistance (ADR) over time has been documented in high-income settings, but data on the determinants of this phenomenon are lacking. We tested the hypothesis that in heavily ARV-experienced patients in the Mexican ARV therapy (ART) roll-out program, the drop in ADR would be associated with changes in ARV drug usage. Genotypic resistance tests obtained from 974 HIV-infected patients with virologic failure and at least 2 previously failed ARV regimens from throughout the country were analyzed for the presence of nRTI, NNRTI and PI resistance-associated mutations (RAMs)...
January 17, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28094084/incontinence-and-psychological-symptoms-in-individuals-with-mowat-wilson-syndrome
#12
Justine Niemczyk, Stewart Einfeld, David Mowat, Monika Equit, Catharina Wagner, Leopold Curfs, Alexander von Gontard
BACKGROUND: Mowat-Wilson Syndrome (MWS) is caused by deletion/mutation of the ZEB2 gene on chromosome 2q22. MWS is characterized by a distinctive facial appearance, severe intellectual disability and other anomalies, e.g. seizures and/or Hirschsprung disease (HSCR). Most individuals have a sociable demeanor, but one third show psychological problems. AIMS: The aim was to investigate incontinence and psychological problems in MWS. METHODS AND PROCEDURES: 26 children (4-12 years), 13 teens (13-17 years) and 8 adults (>18years) were recruited through a MWS support group...
January 13, 2017: Research in Developmental Disabilities
https://www.readbyqxmd.com/read/28093659/clinical-and-molecular-relevance-of-mutant-allele-tumor-heterogeneity-in-breast-cancer
#13
Ding Ma, Yi-Zhou Jiang, Xi-Yu Liu, Yi-Rong Liu, Zhi-Ming Shao
PURPOSE: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data. METHODS: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment...
January 16, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28093068/potential-of-gene-drives-with-genome-editing-to-increase-genetic-gain-in-livestock-breeding-programs
#14
Serap Gonen, Janez Jenko, Gregor Gorjanc, Alan J Mileham, C Bruce A Whitelaw, John M Hickey
BACKGROUND: This paper uses simulation to explore how gene drives can increase genetic gain in livestock breeding programs. Gene drives are naturally occurring phenomena that cause a mutation on one chromosome to copy itself onto its homologous chromosome. METHODS: We simulated nine different breeding and editing scenarios with a common overall structure. Each scenario began with 21 generations of selection, followed by 20 generations of selection based on true breeding values where the breeder used selection alone, selection in combination with genome editing, or selection with genome editing and gene drives...
January 4, 2017: Genetics, Selection, Evolution: GSE
https://www.readbyqxmd.com/read/28093063/whole-genome-sequence-based-genomic-prediction-in-laying-chickens-with-different-genomic-relationship-matrices-to-account-for-genetic-architecture
#15
Guiyan Ni, David Cavero, Anna Fangmann, Malena Erbe, Henner Simianer
BACKGROUND: With the availability of next-generation sequencing technologies, genomic prediction based on whole-genome sequencing (WGS) data is now feasible in animal breeding schemes and was expected to lead to higher predictive ability, since such data may contain all genomic variants including causal mutations. Our objective was to compare prediction ability with high-density (HD) array data and WGS data in a commercial brown layer line with genomic best linear unbiased prediction (GBLUP) models using various approaches to weight single nucleotide polymorphisms (SNPs)...
January 16, 2017: Genetics, Selection, Evolution: GSE
https://www.readbyqxmd.com/read/28092962/effects-of-selection-and-mutation-on-epidemiology-of-x-linked-genetic-diseases
#16
Francesca Verrilli, Hamed Kebriaei, Luigi Glielmo, Martin Corless, Carmen Del Vecchio
The epidemiology of X-linked recessive diseases, a class of genetic disorders, is modeled with a discrete-time, structured, non linear mathematical system. The model accounts for both de novo mutations (i.e., affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Assuming that the population is constant over generations and relying on Lyapunov theory we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive...
June 1, 2017: Mathematical Biosciences and Engineering: MBE
https://www.readbyqxmd.com/read/28092685/precision-oncology-for-acute-myeloid-leukemia-using-a-knowledge-bank-approach
#17
Moritz Gerstung, Elli Papaemmanuil, Inigo Martincorena, Lars Bullinger, Verena I Gaidzik, Peter Paschka, Michael Heuser, Felicitas Thol, Niccolo Bolli, Peter Ganly, Arnold Ganser, Ultan McDermott, Konstanze Döhner, Richard F Schlenk, Hartmut Döhner, Peter J Campbell
Underpinning the vision of precision medicine is the concept that causative mutations in a patient's cancer drive its biology and, by extension, its clinical features and treatment response. However, considerable between-patient heterogeneity in driver mutations complicates evidence-based personalization of cancer care. Here, by reanalyzing data from 1,540 patients with acute myeloid leukemia (AML), we explore how large knowledge banks of matched genomic-clinical data can support clinical decision-making. Inclusive, multistage statistical models accurately predicted likelihoods of remission, relapse and mortality, which were validated using data from independent patients in The Cancer Genome Atlas...
January 16, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28091804/baseline-results-from-the-uk-signify-study-a-whole-body-mri-screening-study-in-tp53-mutation-carriers-and-matched-controls
#18
Sibel Saya, Emma Killick, Sarah Thomas, Natalie Taylor, Elizabeth K Bancroft, Jeanette Rothwell, Sarah Benafif, Alexander Dias, Christos Mikropoulos, Jenny Pope, Anthony Chamberlain, Ranga Gunapala, Louise Izatt, Lucy Side, Lisa Walker, Susan Tomkins, Jackie Cook, Julian Barwell, Vicki Wiles, Lauren Limb, Diana Eccles, Martin O Leach, Susan Shanley, Fiona J Gilbert, Helen Hanson, David Gallagher, Bala Rajashanker, Richard W Whitehouse, Dow-Mu Koh, S Aslam Sohaib, D Gareth Evans, Rosalind A Eeles
In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated...
January 16, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28091594/functional-analysis-reveals-that-rbm10-mutations-contribute-to-lung-adenocarcinoma-pathogenesis-by-deregulating-splicing
#19
Jiawei Zhao, Yue Sun, Yin Huang, Fan Song, Zengshu Huang, Yufang Bao, Ji Zuo, David Saffen, Zhen Shao, Wen Liu, Yongbo Wang
RBM10 is an RNA splicing regulator that is frequently mutated in lung adenocarcinoma (LUAD) and has recently been proposed to be a cancer gene. How RBM10 mutations observed in LUAD affect its normal functions, however, remains largely unknown. Here integrative analysis of RBM10 mutation and RNA expression data revealed that LUAD-associated RBM10 mutations exhibit a mutational spectrum similar to that of tumor suppressor genes. In addition, this analysis showed that RBM10 mutations identified in LUAD patients lacking canonical oncogenes are associated with significantly reduced RBM10 expression...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28091521/mechanisms-of-intrinsic-resistance-and-acquired-susceptibility-of-pseudomonas-aeruginosa-isolated-from-cystic-fibrosis-patients-to-temocillin-a-revived-antibiotic
#20
Hussein Chalhoub, Daniel Pletzer, Helge Weingart, Yvonne Braun, Michael M Tunney, J Stuart Elborn, Hector Rodriguez-Villalobos, Patrick Plésiat, Barbara C Kahl, Olivier Denis, Mathias Winterhalter, Paul M Tulkens, Françoise Van Bambeke
The β-lactam antibiotic temocillin (6-α-methoxy-ticarcillin) shows stability to most extended spectrum β-lactamases, but is considered inactive against Pseudomonas aeruginosa. Mutations in the MexAB-OprM efflux system, naturally occurring in cystic fibrosis (CF) isolates, have been previously shown to reverse this intrinsic resistance. In the present study, we measured temocillin activity in a large collection (n = 333) of P. aeruginosa CF isolates. 29% of the isolates had MICs ≤ 16 mg/L (proposed clinical breakpoint for temocillin)...
January 16, 2017: Scientific Reports
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